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Intestinal homeostasis requires codependent interactions between the intestinal epithelium, the microbiota and the immune system. Innate lymphoid cells (ILCs) play critical roles in intestinal homeostasis, the regulation of intestinal epithelial cell barrier integrity and in immunity to intestinal infections. Dysregulation of ILC responses are associated with multiple chronic human diseases, including IBD, implicating a role for ILCs in immune-mediated pathology. To address the question whether and to which extent innate lymphoid cell (ILC) development and function in gut-associated lymphoid tissues (GALT) are regulated by stromal cells, we will use Ccl19-cre mice that facilitate in vivo targeting of fibroblastic reticular cells (FRCs) in secondary lymphoid organs. FRC-specific ablation of lymphotoxin-beta receptor (LTbR)- and Toll-like receptor (TLR)-signaling revealed that ILC function was substantially deterred following bacterial and viral infection, respectively. One main goal of this project will be to establish a non-infectious animal model using dextran sulfate sodium (DSS)-induced epithelial tissue damage that closely resembles the pathological features seen in patients suffering from IBD. Furthermore, an acute and chronic DSS-colitis model will be examined to study the impact of intestinal FRCs on the induction of ILC effector functions promoting intestinal inflammation using Ccl19-cre mice. In summary, the proposed project will address an important question with clinical relevance.